Suppression of PC-1/ENPP-1 expression improves insulin sensitivity in vitro and in vivo

摘要: Plasma cell membrane glycoprotein-1, or ectonucleotide pyrophosphatase/phosphodieterase (PC-1/ENPP1) has been shown to inhibit insulin signaling in cultured cells vitro and transgenic mice vivo when overexpressed. Furthermore, both genetic polymorphism increased expression of PC-1 have reported be associated with type 2 diabetes humans. Thus it was proposed that inhibition represents a potential strategy for the treatment diabetes. However, not proven suppression its function will actually improve sensitivity. We show current study transient overexpression inhibits insulin-stimulated receptor tyrosine phosphorylation HEK293 cells, while knockdown siRNA significantly increases Akt HuH7 human hepatoma cells. Adenoviral vector expressing short hairpin RNA against mouse (PC-1shRNA) utilized efficiently livers db/db mice. In comparison treated control virus, PC-1shRNA adenovirus had approximately 80% lower hepatic mRNA levels, 30% ambient fed plasma glucose, 25% fasting improved oral glucose tolerance. Taken together, these results demonstrate improves sensitivity an animal model diabetes, supporting proposition is therapeutic approach